Photochemical Behavior of Some Estrone Aryl and Methyl Sulfonates in Solution: Preparative and Mechanistic Studies

Article abstract of DOI:10.1111/php.13272

Direct irradiation of estrone aryl and methyl sulfonates in different organic solvents under nitrogen atmosphere was investigated under steady-state conditions. The estrone derivatives reacted efficiently through the photo-Fries rearrangement reaction involving [1;3]-sulfonyl migration providing the ortho-sulfonyl estrone derivatives and estrone as the photoproducts. In addition, estrone and 2-arylsulfonyl estrone derivatives were epimerized involving a Norrish Type-I reaction. Chemical quenching and photosensitization experiments on the photoreaction have been also carried out to establish the photoreactive excited state. Likewise, the solvent effect and the nature of the sulfonyl group on the photoreactions have been also studied.

Full text of DOI:10.1111/php.13272

DR. SERGIO BONESI (Orcid ID : 0000-0003-0722-339X)
Article type : Special Issue Research Article
Photochemical behavior of some estrone aryl and methyl sulfonates in solution: Preparative and
mechanistic studies†
Matías I. Quindt1,2, Gabriel F. Gola1,3, Javier A. Ramirez1,3 and Sergio M. Bonesi*1,2
1Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química
Orgánica. Buenos Aires, Argentina.
2CONICET – Universidad de Buenos Aires. Centro de Investigaciones en Hidratos de Carbono
(CIHIDECAR). Buenos Aires, Argentina.
3CONICET – Universidad de Buenos Aires. Unidad de Microanálisis y Métodos Físicos Aplicados a
Química Orgánica (UMYMFOR). Buenos Aires, Argentina
*Corresponding author e-mail: smbonesi@qo.fcen.uba.ar (Sergio Mauricio Bonesi)
†This article is part of a Special Issue commemorating the XIV ELAFOT Conference held from
November 11th to 14th, 2019 in Viña del Mar, Chile.
This article has been accepted for publication and undergone full peer review but has not been through
the copyediting, typesetting, pagination and proofreading process, which may lead to differences
between this version and the Version of Record. Please cite this article as doi: 10.1111/PHP.13272
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ABSTRACT
Direct irradiation of estrone aryl and methyl sulfonates in different organic solvents under nitrogen
atmosphere was investigated under steady-state conditions. The estrone derivatives reacted efficiently
through the photo-Fries rearrangement reaction involving [1;3]-sulfonyl migration providing the
ortho-sulfonyl estrone derivatives and estrone as the photoproducts. In addition, estrone and 2-
arylsulfonyl estrone derivatives were epimerized involving a Norrish Type I reaction. Chemical
quenching and photosensitization experiments on the photoreaction have been also carried out to
establish the photo reactive excited state. Likewise, the solvent effect and the nature of the sulfonyl
group on the photoreactions have been also studied.
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INTRODUCTION
Estrone and estradiol are steroidal sex hormones possessing significant physiological activity and have
attracted the attention of organic chemists promoting the development of new and challenging total
synthesis (1, 2). These estrogens are involved in many biological processes and certainly, drugs
bearing steroidal motifs are used for the treatment of different medical conditions (3). Thus, novel
potent inhibitors of 17-hydroxy steroids dehydrogenase type 1 (17-HSD) bear the estrone motif
where the position at carbon 6, 16, or 17 have been modified (4). This enzyme can be found in all
classical steroidogenic tissues, all peripheral tissues, including the skin and breast, and moreover, it is
highly expressed in malignant breast cells (5). 3-Hydroxyestra-1,3,5(10)-trienyl toluene-p-sulfonate
was found to be one of the best inhibitors of estrone sulfatase activity exhibiting an inhibitory activity
close to that of estrone-3-methylthiophosphonate (E1-3-MTP), one of the classical potent inhibitor
known (6). Likewise, alkylsulfonate derivatives of estrone; i.e., the methanesulfonate, the
ethanesulfonate and the butanesulfonate, all showed some inhibition of estrone sulfatase but not at
levels of the estrone toluene-p-sulfonate (7). Therefore, sulfonylation of the estrone moiety could
provide a new family of derivatives with the potential ability to inhibit the estrone sulfatase activity in
regulating estrogen production. The synthetic 17-ethinylestradiol, a phenolic steroid, is responsible
for the development of secondary sexual characteristics in female vertebrates (8).
The photochemical behavior of steroids in solution was completely studied in terms of
photorearrangement, photoaddition, photoreduction and photooxidation reactions throughout the years
(9), and photochemical approaches toward the synthesis of natural products have been applied with
success (10). The photochemistry of steroids have been studied in terms of preparative, mechanistic
and taking into account the stereospecificity of the photoreaction and some interesting examples are
depicted in Scheme 1 (11-19). Indeed, photoinduced lactonization reaction of some cholestan-6-one
derivatives provided efficiently 6-oxa-B-homocholestan-7-ones with retention of the configuration at
C-5 (12). Likewise, direct irradiation of 3-(dimethylphenylsilyloxy)-5-androstane-6,17-dione and
its 3 isomer gave two distinct photoproducts arising from the photoreduction and the Norrish type I
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reactions of the steroids. An antenna-photosensitization process from the arylsilyloxy group to the
carbonyl groups through triplet and singlet energy transfers accounts for this particular behavior (16).
Direct irradiation of estrone and estrone 3-methyl ether showed the epimerization of methyl
group at C-13 located at ring D of the steroids involving a Norrish Type I reaction (see Scheme 1).
Also, seco-steroids as byproducts were formed when anhydrous THF was used as solvent (20).
Irradiation of estrone with UV-B (280 – 320 nm) led to the almost complete conversion into
lumiestrone in acetonitrile as well as in water under aerobic conditions (21). These results confirmed
that 13-epimerization reaction occurred through the Norrish type I mechanism which is typically
observed with cyclic ketone moiety (22). The photocatalytic azolylation reaction of estrone methyl
ether, a precursor leading to an FDA approved oral contraceptive (mestranol), have been reported by
Weaver and co-workers and they were able to isolate the desired estrone derivative in 37% yield as a
single regioisomer in which the benzothiazolylation occurred at C4 position of the estrone 3-methyl
-
-
ether (23). Recently, the photodegradation of estrone and 17-ethinylestradiol with HCO3 , NO3 and
254 nm photolysis has been reported (24) because these steroids are considered as toxic contaminants
of emerging concerns (CECs) for water reused applications. Estrogens were also photooxidized
efficiently with humic acids in the presence of Mn(III) (25) and the application of alkene
cyclopropanation with chloromethyl silicate through a visible-light-mediated redox neutral catalysis of
vinylphosphonate derived from estrone took place efficiently and the photoproduct was isolated in
92% yield (26).
<Insert Scheme 1>
However, the direct irradiation (254 nm) of estrone arylsulfonate and estrone methylsulfonate was not
previously reported yet in the literature, we were encouraged to undertake a more extensive work and
to study accurately the reaction mechanism for which we chose as the substrates the estrone
derivatives that are shown on Chart I.
<Insert Chart I>
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These estrone derivatives 1 – 4 bearing a sulfonic ester group on the phenyl ring of the steroids,
became interesting substrates to study the possible photo-Fries rearrangement under direct irradiation
(exc = 254 nm). Anderson and Reese (27) have discovered the photo-Fries rearrangement reaction in
1960 and later it was demonstrated that the photoreaction involves the homolytic fragmentation of the
carbon–heteroatom bond, i.e., C-O, C-S and C-N, characteristic bonds present in esters, thioesters and
amides, respectively (28). Usually, the photoreaction provided the ortho- and para-regioisomers along
with the corresponding phenols, thiophenols or amines, depending on the nature of the carbon-
heteroatom bond cleaved (29). Also, it was established that the photoreaction involved an in-cage
radical mechanism and it is known that the singlet state is the photo reactive excited state (29). The
preparation of griseofulvin (30), daunomycinone (31) and flavonoids (32) have successfully employed
the photo-Fries rearrangement reaction, however, most of the studies have been devoted to elucidating
the mechanism of the reaction rather than its application as a synthetic methodology. In addition, we
have also contributed to show how important is the application of the photo-Fries rearrangement
reaction in the preparation of 2,2-dimethyl-4-chromanone derivatives (33, 34) and carbazole
derivatives (35, 36). Recently, we were able to show the selectivity and the effect of surfactant
micelles on the photo-Fries reaction of an assortment of substituted acetamides (37) as well as
substituted aryl benzoates (38) and also, the photochemical behavior of 3-aryloxy estrone derivatives
in solution (39).
Therefore, we present herein our work on the direct irradiation of estrone derivatives 1 – 4 (see
Chart I) in term of product distribution, triplet photosensitization and chemical quenching of the
photochemical reaction.
MATERIALS AND METHODS
Materials and equipment. Estrone, tetramethyl-diazodiazetine dioxide, benzene sulfonyl chloride,
pyridine, p-methylphenyl sulfonyl chloride and acetone were obtained from commercial sources.
Spectroscopic grade solvents were used as received but pyridine was first distilled and immediately
stored over KOH pellets. A Fisher Jones apparatus was used to determine the Melting Points and were
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not corrected. NMR spectra were recorded on a 500 MHz spectrometer using CDCl3 as the solvent.
Chemical shifts ( are reported in parts per million (ppm), relative to the internal standard signal of
tetramethylsilane. 2D NMR spectra (HSQC and HMQC sequences) were also recorded in CDCl3 on
the same spectrometer. All the mono and bi-dimensional measurements were carried out using
standard pulse sequences and the coupling constant (J) values were given in Hz. A Shimadzu UV-
1203 spectrophotometer was used to record the UV-visible spectra using two-faced stoppered quartz
cuvettes (1 mm x 1 mm) at 298 K. HR-MS (ESI) analyses were performed on a Bruker micrOTOF-Q-
11 instrument. Quadrupole – time of flight analyzer that provides exact masses with an error less than
3 ppm in EM and less than 5 ppm in EM/MS.
General Procedure for the Synthesis of estrone aryl and methane sulfonates 1, 3 and 4. Estrone (1.85
mmol) was dissolved in pyridine (10 mL) and the solution was placed in an ice-bath. Then, the
corresponding sulfonyl chloride (2.22 mmol) was added dropwise to the solution during 10 minutes
under gentle stirring. The solution was stirred at 25 ºC until positive control by TLC. Then, the
reaction mixture was extracted with dichloromethane (10 mL) and washed with a solution of diluted
HCl (10 mL). The organic phase was washed with water, dried over sodium sulfate, filtrated off and
finally, was evaporated under vacuum. The solid was washed with 10 mL of methanol at 0/5 °C and it
was dried in the air. The corresponding sulfonates were obtained in good yields. Compounds 1, 3 and
4 were fully characterized by physical and spectroscopic data (1H and 13C NMR) (see Supporting
Information).
General Procedure for the Synthesis of estrone 4-fluorophenyl sulfonate 2. 4-Fluorobenzene-1-
sulfonyl chloride was prepared following the methodology previously reported in the literature with
some slight modifications (40). Preparation of estrone 4-fluorophenyl sulfonate 2 with the 4-
fluorobenzene-1-sulfonyl chloride in pyridine was performed by the sulfonylation method previously
described giving 2 as a white solid after purification by flash chromatography on silica gel using
mixtures of hexane and ethyl acetate as the eluent (0.46 g, 88%). Compounds 4-fluorobenzene-1-
sulfonyl chloride and 2 were fully characterized by physical and spectroscopic data (1H and 13C NMR)
(see Supporting Information).
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General Procedure for the Synthesis of compounds 7, 8 and 9. The preparation of compound 7 was
performed according to the methodology reported in the literature (39). Next, the preparation of
norestrone phenyl sulfonate 8 and norestrone methane sulfonate 9 with benzenesulfonyl chloride and
methanesulfonyl chloride, respectively, was performed according to the method previously described
giving compounds 8 and 9 in good yields and these compounds were fully characterized by physical
and spectroscopic data (1H and 13C NMR) (see Supporting Information).
General procedure for the irradiation of estrone aryl and methane sulfonates. The general procedure
for the irradiation of compounds 1 – 4, 8 and 9 were performed according to the methodology reported
in the literature (39). The photoproducts were isolated and characterized by mean of physical and
spectroscopic methods (see Supporting Information).
General Procedures for Potentiometric Titrations. A stock solutions of sulfonates (1, 3 and 4, 0.106
mmol) in acetonitrile or methanol were irradiated for 15, 30, 60, 120 and 150 min, under nitrogen
atmosphere. Known volumes of these irradiated solutions were diluted to 100 mL with deionized
water. The extent of photoacid generation was determined by titration using a validated solution of
NaOH 0.0212 N. Potentiometric titrations were performed using a standard proton glass electrode and
a pH meter Cole-Parmer Chemcadet 5986-50.
Preparation of the relative yield profiles. The relative yield profiles were constructed as follow.
Aliquots of the reaction mixture were picked up at different irradiation times and each aliquot was
evaporated leading to a solid residue that was dissolved in deuterated chloroform. Then, the 1H-NMR
spectra of the solutions were recorded. Finally, the aromatic protons of the aryl ring of the steroid
derivatives were chosen as the diagnostic signals and, after integration of these signals, the yields were
calculated.
RESULTS
Irradiation of estrone aryl sulfonate in solution.
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Direct irradiation with exc = 254 nm of estrone benzene sulfonate (1), estrone p-fluorobenzene
sulfonate (2) and estrone p-methylbenzene sufonate (3) in cyclohexane and methanol under nitrogen
atmosphere gave the following photoproduct distribution which are the expected ones from the photo-
Fries rearrangement, viz. the ortho regioisomers (1a and 1b from compound 1, 2a and 2b from
compound 2 and 3a and 3b from compound 3), and estrone (5). Additionally, lumiestrone (6) was
detected in the reaction mixtures and compounds 1c, 2c and 3c were also detected in the reaction
mixture after irradiation of estrone benzene sulfonate (1), estrone p-fluorobenzene sulfonate (2) and
estrone p-methylbenzene sulfonate (3), respectively. The photo-Fries rearrangement reactions of the
estrone sulfonate derivatives are depicted in Scheme 2.
<Scheme 2>
On the other hand, when the irradiations of the estrone aryl sulfonates (1 – 3) were carried out
in acetonitrile the product distribution was completely different. Indeed, estrone (5) and lumiestrone
(6) were the only products detected in the reaction mixtures being estrone the main product in all the
cases. Also, irradiation with UV-light (254 nm) of compound 1 in tetrahydrofuran provided
lumiestrone 6 in quantitative yield. These polar aprotic solvents (acetonitrile and tetrahydrofuran)
change completely the course of the photoreaction favoring the photoinduced solvolysis of the
sulfonic esters 1, 2 and 3 providing exclusively estrones 5 and 6 and cancelling the [1;3]-migration of
the arylsulfonyl group to give the ortho-regioisomers. We have selected three different reaction
solvents showing distinct polarity and proticity properties in order to study their effect on the
photochemical behavior of the estrone sulfonate derivatives, a procedure that is often applied when
photochemical reactions are studied for the first time.
Table 1 shows the chemical yields of the photoproducts formed. It is apparent from the data
that the ortho-regioisomers are the main photoproducts obtained when the reaction solvent was
cyclohexane. In fact, the (a+ b + c) / (5 + 6) ratios change from 3.1 to 4.2, always favoring the
formation of the ortho-regioisomers over the estrones, but the ratios change only from 1.1 to 1.7 when
the solvent is methanol. On the other hand, the data displayed in the table also shows that the [1;3]-
migration of the arylsulfonyl group is preferred to position 4 of the aryl moiety over the migration of
the same group to position 2 and certainly does not depend significantly on the reaction solvent as can
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be seen from the (b/a) ratio that have a 2.3 mean value in both reaction solvents. The low selectivity
of the migration observed for the aryl sulfonyl group to carbon 2 can be attributed to the steric
electronic effect due to the ring B of the steroid.
<Insert Table 1>
The quantum yields (R) assigned to the consumption of estrone arylsulfonates (1, 2 and 3)
were also measured (see Table 1). The R values of estrone 1 move from 0.010 to 0.020 in all the
solvents used while for esters 2 and 3 the R values are 3 to 5 times lower than 0.02 when the
irradiations were carried out in acetonitrile and cyclohexane, respectively. However, these R values
mean that the photochemical reaction took place smoothly and could compete with radiative and non-
radiative pathways.
The photochemical reaction of the estrone aryl sulfonates 1 – 3 were followed by UV-visible
and NMR spectroscopies. Figure 1(a) and (b) shows the variation of the UV-visible absorption spectra
with the irradiation time of the photochemical reaction of estrone p-fluorobenzene sulfonate (2) in
methanol and estrone p-methylbenzene (3) in cyclohexane. A new absorption band situated at 300 nm
is formed and rises with irradiation time in the above-mentioned solvents. The new bands were
assigned to the electronic transition of the sulfonyl group of the ortho-regioisomers (42) and it was
found that the position of the new band was not affected upon solvent polarity change. Similar
spectroscopic behavior was observed for estrone benzene sulfonate (1) in both cyclohexane and
methanol.
Figure 1(c) outlines the course of the photochemical reaction of ester 2 in methanol measured
by NMR spectroscopy where it can be deduced that the migration of the p-fluorobenzene sulfonyl
group is the main reaction pathway providing ortho-regioisomers 2a, 2b and 2c. Diagnostic signals
(aromatic protons) of the estrone derivatives (2, 2a, 2b, 2c, 5 and 6) were accurately selected and,
after integration of these signals, the yields were calculated. Similar results were obtained when the
course of the photoreaction was carried out in cyclohexane. Notably, the sum of the yields of estrone
(5) and lumiestrone (6), respectively, was lower than 22% in cyclohexane while in methanol was
lower than 43%. Figure 1(d) shows the relative formation of compounds 2a, 2b and 2c finding that
similar relative rates were obtained in methanol as well as in cyclohexane. The finding leads to the
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conclusion that radiative and non-radiative decay competitively with the photochemical reaction
pathway.
<Insert Figure 1>
On the other hand, it is apparent from the relative yield profile shown in Figure 1(c) that the
photoinduced Norrish Type I reaction competes with the photo-Fries rearrangement reaction during
the irradiation of estrone 2. Effectively, both photoproducts 2a and 5, respectively, reached a
maximum yield value at ca. 60 minutes and then, each compound was consumed at distinct rate. This
behavior was attributed to the epimerization of the methyl group at C-13 of the nucleus D of the
estrone moiety in compounds 2a and 5, respectively. Indeed, irradiation of compound 2a at 254 nm
provides efficiently compound 2c in 11% through a Norrish Type I mechanism involving the
epimerization of methyl group (see Scheme 3). No epimerization of region isomer 2b occurred during
irradiation of ester 2. Likewise, estrone (5) was converted smoothly to lumiestrone (6) during the
irradiation of estrone p-fluorobenzene sulfonate (2) because of the easily epimerization of the methyl
group attached on the ring D of the steroid (see Scheme 3) (20, 21). The epimerization reaction
observed on compounds 2a and 5, respectively, involves a homolytic fragmentation of the C
attached to the carbonyl group at ring D providing a biradical intermediate as is depicted in Scheme 3.
Then, an intramolecular cyclization pathway provided the epimerized photoproducts, viz. 2c and 6,
respectively. A similar behavior was observed for estrone aryl sulfonates 1 and 3, where compounds
1a, 3a and estrone 5 epimerized efficiently during the photochemical reaction providing compounds
1c, 3c and lumiestrone 6, respectively.
<Insert Scheme 3>
Figure 2 shows the course of the epimerization of estrone 5 into lumiestrone 6 which are
formed during the irradiation of estrone p-fluorophenyl sulfonate 2 in methanol followed by 1H-NMR
spectroscopy. It is apparent from the stacked spectra that the signal with chemical shift at 0.90 ppm
assigned to the methyl group at C-13 of estrone 5 diminishes as the reaction time increases while a
new signal with chemical shift of 1.05 ppm that was assigned to the methyl group of lumiestrone 6,
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increases. Therefore, these results demonstrate once again that the epimerization of compound 5
involves the homolytic fragmentation of the  carbon through the Norrish Type I reaction mechanism.
<Insert Figure 2>
The noticeable photo stability observed for compounds 1b, 2b and 3b during irradiation of
estrone sulfonates 1, 2 and 3 can be ascribed to the strong intramolecular hydrogen bonding between
the thionyl group and the hydroxy group of the -hydroxysulfone moiety which is present in the
aromatic ring A of the steroid (see Scheme 4). Excitation with light of 254 nm of compounds 1b, 2b
and 3b bearing a -hydroxy sulfone group in their structures, the * excited states are populated
efficiently where the thionyl group becomes more basic and the phenolic group usually becomes more
acidic favoring the excited state intramolecular proton transfer (ESIPT) process that then follows the
deactivation pathways (radiative and non-radiative pathways). Therefore, the epimerization of the
methyl group at C-13 of compounds 1b, 2b and 3b, respectively, was not observed and no
competition with deactivation pathways occurred. A similar behavior has been early observed for 3-
acyl estrone derivatives (39). On the other hand, epimerization of compounds 1a, 2a and 3a to
photoproducts 1c, 2c and 3c, respectively, is due to the non-planarity of the arylsulfonyl group with
the benzene moiety disfavoring the intramolecular hydrogen bonding between the thionyl group and
the hydroxyl group. Therefore, in these cases the ESIPT process is not a competitive pathway and the
epimerization reaction of the carbonyl group proceeds smoothly because an intramolecular triplet
photosensitization process occurs from the aryl moiety to the carbonyl group at C-17 of compounds
1c, 2c and 3c accordingly with was previously reported in the literature for 3-dimethylphenylsilyloxy
androstanone derivatives (16, 43) and 3-acylestrone derivatives (39).
<Insert Scheme 4>
Chemical quenching and photoinduced sensitization of the photo-Fries rearrangement of
estrone aryl sulfonates.
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The multiplicity of the photo reactive excited state that led to the photo-Fries rearrangement reaction
of estrone phenyl sulfonate (1) was determined performing triplet sensitization of the photoreaction
with acetone and triplet energy quenching with tetramethyl-1,2-diazetine dioxide (TMDO). Triplet
photosensitization of photo-Fries rearrangement of estrone 1 was carried out in acetone because
acetone was the triplet energy donor while estrone 1 was the triplet energy acceptor. Indeed, the ET of
acetone (44) is 74 kcal.mol-1 while the ET of estrone phenyl sulfonates was assumed to be 69.4
kcal.mol-1 (45) considering the phenyl sulfonate group does not modify substantially the value of the
estrone moiety. Therefore, the triplet energy transfer pathway was a thermodynamically feasible
process by ca. 5 kcal.mol-1. Then, irradiation of estrone phenyl sulfonate 1 was carried out with exc
=
310 nm in acetone and the results are collected in Table 2. The data in the Table 2 indicates that
irradiation of estrone 1 in acetone provided a distinct photoproduct distribution when compared with
the results obtained in cyclohexane. Indeed, the photosensitized reaction provided estrone 5 and
lumiestrone 6 as the sole photoproducts while the ortho-regioisomers 1a and 1b were not formed.
Noteworthy, the yield of estrone 5 increased four times while the yield of lumiestrone 6 was doubled
under acetone photosensitization.
<Insert Table 2>
We have also studied the quenching of the photo-Fries rearrangement by tetramethyl-1,2-
diazetine dioxide (TMDO) which is a triplet energy quencher (ET = 54.0 kcal.mol-1)(36) and we were
able to show that the energy gap between its triplet state and that of estrone 1 was of ca. 15 kcal.mol-1
and we concluded that the triplet energy transfer pathway is hence possible. Then, irradiation of
estrone phenyl sulfonate 1 in cyclohexane but in the presence of increasing amounts of TMDO
showed that the photo-Fries rearrangement reaction proceeded efficiently while the yields of estrone 5
and lumiestrone 6 diminished significantly (see Table 2). Therefore, after accurate rationalization of
the results, we can conclude that: (i) the excited triplet state of estrone phenyl sulfonate 1 is not the
photo reactive state in the photo-Fries rearrangement reaction and, (ii) the conversion of estrone 5 into
lumiestrone 6 certainly involves the triplet excited state because the photoepimerization reaction was
efficiently quenched by TMDO. The photoepimerization reaction of estrone 5 is in agreement with
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similar results reported in the literature such as the involvement of a triplet state in the
photoepimerization reaction of cyclic ketones (16, 43, 46). Likewise, we have previously
demonstrated that direct irradiation of estrone methyl ether furnished lumiestrone methyl ether
involving the photoepimerization of methyl group at C-13 through a Norrish type I mechanism (39).
Furthermore, we have also assessed that the photoepimerization reaction of estrone methyl ether was
efficiently quenched by TMDO and was sensitized by acetone confirming that the triplet excited state
is the photo reactive excited state of the photoreaction. Finally, we can conclude from these
experiments that the photo-Fries rearrangement reaction of estrone aryl sulfonates takes place from the
singlet excited state (S1) while the photo epimerization of estrone proceeds from the triplet excited
state (T1).
Irradiation of estrone methyl sulfonate (4) in homogeneous media.
Surprisingly, irradiation with exc = 254 nm of estrone methane sulfonate 4 in different solvents under
nitogen atmosphere did not provide the expected photo-Fries photoproducts, instead, a noticeable
distinct product distribution was obtained, viz. compounds 4a, 4b and lumiestrone 6 as it is depicted
in Scheme 5(a). Table 3 also showed the chemical yields of the photoproducts.
<Insert Scheme 5>
Table 3 showed that direct irradiation of estrone methane sulfonate 4 in cyclohexane and
acetonitrile gave compound 4a in good yield being the main photoproduct. In the case the reaction
was carried out in acetonitrile, lumiestrone 6 was also detected but in only 7% yield. The conversion
of 4 into 4a was attributed to the photo epimerization of the methyl group (the C-13 located at the ring
D of compound 4) through a Norrish Type I photoreaction that proceeded efficiently in both reaction
solvents. Furthermore, formation of lumiestrone 6 turned out to be the hydrolysis of compound 4a as
well as the starting material (4).
<Insert Table 3>
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The course of the photoreaction of estrone 4 in acetonitrile was measured by NMR
spectroscopy as it is outlined in Figure 3 where the epimerization of the methyl group at C-13 is the
main reaction pathway providing photoproduct 4a. The relative yield profile was constructed choosing
the methyl protons of the steroid derivatives (4, 4a and 6) and the yields of the steroids were
calculated after integration of the signals.
<Insert Figure 3>
When the photoreaction was carried out in methanol compound 4b was formed in 70% yield
along with 4a and 6 in lower yields (up to 15%). Interestingly, the origin of compound 4b and 4a
involves the same biradical intermediate A which is obtained through a Norrish type I mechanism.
Meanwhile, intermediate A evolves to 4a through an epimerization pathway, it is apparent that the
same intermediate is able to involve competitively an intermolecular hydrogen abstraction from the
reaction solvent releasing intermediate B. Oxidation of intermediate B by residual molecular oxygen
and further reaction with methanol, affords compound 4b (see Scheme 5(b)). This photochemical
behavior was also observed during irradiation of estrone methyl ether (39).
Irradiation of 17-norestrone phenyl sulfonate (8) and 17-norestrone methyl sulfonate (9)
in homogeneous media
We decided to synthetize 17-norestrone phenyl sulfonate 8 and 17-norestrone methyl sulfonate 9 as
probe compounds with the aim to demonstrate that the carbonyl group (C-17 at the ring D of the
steroid) is responsible of the competitive Norrish type I reaction during the irradiation of estrones 1, 2
and 3. The preparation of both compounds 8 and 9 involves the application of the Wolf-Kischner
reaction on estrone 5 providing 17-norestrone 7 in good yield (91%) (39). Then, treatment of 17-
norestrone 7 with benzenesulfonyl chloride in pyridine at room temperature gave compound 8 in 88%
yield while treatment of compound 7 with methanesulfonyl chloride compound 9 was obtained in
95% yield (see Scheme 6).
<Insert Scheme 6>
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Irradiation of 17-norestrone benzene sulfonate (8) in methanol and cyclohexane (exc = 254
nm) under nitrogen atmosphere provided the ortho-regioisomers 8a and 8b and the corresponding 17-
norestrone (7) (see Scheme 6) as the sole photoproducts when the ester 8 was consumed in up to 90%
yield because compound 8 does not bear a carbonyl group at C-17 and, therefore, no photo
epimerization of the photoproducts occurred. The selectivity of the benzene sulfonyl group migration
did not depend on the reaction solvent used because the 8a/8b ratio was found to be ca. 1.2 in both
solvents. On the other hand, irradiation of estrone methane sulfonate 9 in methanol provided the
expected ortho-regioisomers (9a and 9b) in good yield and no epimerization reaction was observed.
The quantum yields of consumption (R) of 8 and 9 were also measured and were found to be similar
(see Scheme 6). Taking into account that the obtained R values are ten-times lower than those
obtained for compounds 1 and 4, respectively, we can suggest that the photo-Fries rearrangement of
compounds 8 and 9 proceeded smoothly and radiative and non-radiative decay processes are the solely
pathways that compete with the photochemical reaction.
Estrone sulfonates as photoacid generators in acetonitrile.
In order to explain the distinct photochemical behavior observed for estrone aryl and methane
sulfonates in acetonitrile (see Tables 1 and 3), we decided to measure potentiometrically the amount
of sulfonic acid evolved at different irradiation time when solutions of estrones 1, 3 and 4 were
irradiated with light of 254 nm in acetonitrile. Figure 4(a) shows the potentiometric titration curves of
compound 1 at different irradiation time using a validated solution of NaOH 0.0212 mol.dm-3.
Certainly, this plot turns out that an acidic photoproduct is formed as the irradiation time increases
from 15 to 180 min. Indeed, we can suggest that upon irradiation of estrone benzene sulfonate (1) in
acetonitrile, benzene sulfonic acid was released as well as estrone (5) that, in turn, estrone (5) was
converted into lumiestrone (6) upon irradiation (see Scheme 7). Similar results were obtained for the
other two estrone derivatives.
<Insert Scheme 7>
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On the other hand, Figure 4(b) depicts a nice representation of sulfonic acids formed to
estrones molar ratio as a function of irradiation time of estrone derivatives 1, 3 and 4 in acetonitrile
and in methanol. It is apparent from the plot that during irradiation of the estrone derivatives the
acidity of the solution increases with irradiation time. Therefore, the sulfonic acids released to the
medium promoted the hydrolysis of the starting materials and consequently, estrone 5 is the main
photoproduct formed along with lumiestrone 6 (see Scheme 7). It is apparent from the plots depicted
in Figure 4(b) that estrone aryl sulfonates 1 and 3 reacted efficiently and rapidly in acetonitrile than
estrone 4 did. However, when the solvent is methanol, estrone benzenesulfonate 1 did not released
efficiently significant amounts of the corresponding phenyl sulfonic acid. Similar photochemical acid
generators behavior of aryl sulfonate derivatives have been reported in the literature.(47),(48)
<Insert Figure 4>
DISCUSSION
As hinted above, it was found that the direct irradiation (254 nm) of estrone aryl sulfonates 1, 2 and 3
reacted efficiently in cyclohexane and methanol under nitrogen atmosphere (see Scheme 2 and Figure
1) giving the [1;3]-sulfonyl migrated photoproducts together with estrone (5) (see Table 1).
Additionally, photo epimerization of 1a, 2a and 3a to give compounds 1c, 2c and 3c, respectively,
occurred efficiently as well as estrone (5) was converted into lumiestrone (6) during irradiation. This
behaviour shows that during the irradiation of sulfonates 1, 2 and 3 two reaction pathways certainly
operate: i) the photo-Fries rearrangement reaction and, ii) the Norrish type I reaction. Based on our
results, Scheme 8 depicts the proposed reaction mechanism for the direct irradiation of estrone aryl
sulfonates.
<Insert Scheme 8>
Population of the singlet excited state of estrone aryl sulfonates (1, 2 and 3) was achieved upon
direct irradiation with light of 254 nm. The singlet excited state is the photo reactive state because the
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triplet energy quenching of estrone 1 with TMDO and photosensitization experiments with acetone
(see Table 2) have demonstrated that the triplet excited state is not involved in the photo-Fries
rearrangement of the estrone derivatives. Then, S-O bond cleavage of the sulfonic ester group (path
(a)) takes place efficiently from the excited state and the fragmentation pathway competes with
fluorescence and prompt-heat processes from the same excited state (kd). Two radical species are thus
formed in the solvent cage after S-O bond was broken, viz. the arylsulfonyl and the phenoxy radicals.
These radical species evolve to photoproducts across two competitive pathways: (i) in-cage [1;3]
arylsulfonyl radicals migration to positions 2 and 4 affording the expected ortho-regioisomers (path
(b) in Scheme 8) and, (ii) diffusion of the radical species from the solvent cage giving estrone 5 as
well as the aryl sulfonic ester (path (c) in Scheme 8). Indeed, the phenoxy radical captures a hydrogen
atom from the solvent furnishing estrone (5) while aryl sulfonic acids arise from the reaction of the
aryl sulfonyl radical with residual water contained in the organic solvents. Noteworthy, the
photochemical behavior of the ortho-regioisomers are quite different. In fact, regioisomers 1b, 2b and
3b were photo stable compounds upon irradiation with  = 254 nm while regioisomers 1a, 2a and 3a
were not. This strong photo stability is attributed to the ESIPT process (excited state intramolecular
proton transfer) between the thionyl group and the hydroxy group of the -hydroxysulfone moiety
which is present in the aromatic ring A of the steroid (see Scheme 4) causing the deactivation of these
ortho-regioisomers through radiative and non-radiative pathways. On the other hand, photo-
epimerization reaction of compounds 1a, 2a and 3a took place smoothly providing compounds 1c - 3c
due to out-of-plane deviation of the arylsulfonyl group from the co-planarity of the aromatic ring and
consequently, disfavoring the intramolecular proton transfer process. Therefore, a singlet-singlet
energy transfer occurred efficiently between the aryl moiety and the carbonyl group (C-17) during
direct irradiation (254 nm) of compounds 1a – 3a promoting the population of the triplet excited state
of the carbonyl group (C-17) (see later in the text) (41). Once the triplet state was populated, two
competitive deactivation processes arose: (i) deactivation of the triplet state (k’’d in Scheme 8) that
restores compounds 1a- 3c in their ground states and, (ii) the Norrish Type I photoreaction. Thus, the
Norrish Type I reaction promotes the fragmentation of the C-C=O bond at the ring D of compounds
1a – 3a (path (d)) providing the corresponding biradical intermediates that then, epimerize the methyl
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group at C-13 to give the observed compounds 1c – 3c (path (e)). Similar conclusions can be drawn
for the conversion of estrone 5 into lumiestrone 6 (paths (f) and (g) in Scheme 8) via a Norrish Type I
photoreaction (see also Figure 2) (16, 20). Indeed, quenching with TMDO and photosensitization with
acetone of the Norrish Type I photoreaction of 5 (Table 2) confirm the involvement of a triplet excited
state which is located on the carbonyl group (C-17) of the D ring of the steroid. Therefore, we
concluded that the triplet state of the carbonyl group (C-17) is involved in the photoinduced
epimerization reaction of compounds 1a, 2a, 3a and 5. The way the carbonyl group populates the
triplet excited state was achieved as follows: selective excitation of the phenolic moiety (the antenna
chromophore) to its singlet excited state populates efficiently the carbonyl group (C-17; the acceptor
chromophore) singlet excited state through a singlet-singlet energy transfer because this pathway is a
feasible thermodynamic process (see Scheme 9) (39). Then, the triplet excited state (n,*) of the
carbonyl group is formed through the intersystem crossing process that can compete with the
fluorescence emission process. Finally, we can conclude that the photo-epimerization reaction of the
methyl group took place smoothly from the triplet excited state (T1(n,*)) of the carbonyl group
through a Norrish Type I reaction mechanism. A similar photochemical behavior has been recently
reported for 3-acyl estrone derivatives (39).
<Insert Scheme 9>
Surprisingly, it was observed that direct irradiation of estrone methane sulfonate 4 in
cyclohexane, acetonitrile and methanol under N2 atmosphere did not provide the expected photo-Fries
photoproducts while a noticeable distinct product distribution was obtained depending on the reaction
solvent (see Table 3 and Scheme 5). This photochemical behavior was attributed to the intramolecular
singlet-singlet energy transfer from the antenna chromophore (the phenolic moiety) to the carbonyl
group (C-17; the acceptor chromophore) that evolved to the selective population of the triplet excited
state (n,*) of the last group. Then, C(O)-C homolytic fragmentation from the triplet excited state
occurred and epimerization of the methyl group proceeded smoothly via the Norrish Type I reaction
mechanism. Therefore, the photo-Fries rearrangement of compound 4 did not compete with the
intramolecular singlet-singlet energy transfer.
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Concurrently, it was found that irradiation of estrone aryl sulfonates in acetonitrile released
aryl sulfonic acid behaving as efficient photoacid generators (PAGs). Indeed, after excitation of the
estrone derivatives, consecutive path (a) and path (c) in Scheme 8 proceeded efficiently giving
estrone (5) and aryl sulfonic acids as the sole photoproducts and no competition of the [1;3]-migration
aryl sulfonyl group (path (b)) was observed (see Table 1 and Scheme 7). The apparent photo-
solvolysis observed in acetonitrile can be ascribed to the significant increase of the acidity in the
reaction medium with irradiation time (see Figure 4). Then, a thermal hydrolysis of the estrone aryl
sulfonates (path (h)) took place very efficiently promoting cleanly the formation of estrone (5) that in
turn, after absorption of a photon, was converted into lumiestrone (6) according to path (f) in Scheme
8. The photochemical/thermal behavior described above in acetonitrile was also observed for the
irradiation of compound 1 in tetrahydrofuran (see Table 1).
Finally, direct irradiation (254 nm) of 17-norestrone benzene sulfonate (8) and methane
sulfonate (9) in methanol and cyclohexane gave the expected ortho-regioisomers in good yield and
17-norestrone (7) (see Scheme 6). No epimerization of the photoproducts was observed because the
carbonyl group at C-17 was absence and consequently, the Norrish Type I reaction does not compete
with the photo-Fries rearrangement reaction. Certainly, these results confirmed that if there is no a
carbonyl group at the ring D, no intramolecular singlet-singlet energy transfer occurs and thence, no
epimerization of the methyl group takes place. We suggest that this methodology would be useful in
the synthesis of other kinds of aryl and alkyl sulfone steroid derivatives belonging to the family of
estrone through the photo-Fries rearrangement without interference of the Norrish Type I reaction.
CONCLUSIONS
The photochemical behavior of estrone aryl and alkyl sulfonate derivatives examined in this work
proceeds efficiently giving the ortho-regioisomers and estrone via the photo-Fries rearrangement
reaction and the formation of the ortho-regioisomers depends on the solvent reaction. We were able to
demonstrate that the photoreaction occurs from the singlet excited state through photosensitization
and chemical quenching experiments. The S-O bond cleavage gives in-cage sulfonyl and phenoxyl
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radicals and competes with the excited state deactivation pathways. These radicals can couple in-cage
through a [1;3]-sulfonyl migration to give the desired ortho-regioisomers (see Scheme 8) or can
diffuse to the bulk and give estrone. Compounds 1b, 2b and 3b were found to be photo stable
photoproducts due to the efficient ESIPT processes under UV irradiation (see Scheme 4). On the other
hand, irradiation of estrone (5) and compounds 1a, 2a and 3a with UV light (254 nm) are found to
photoepimerize via a Norrish Type I reaction mechanism (see Schemes 3 and 8) involving the triplet
excited state of the carbonyl group (C-17) (see Scheme 9). Surprisingly, irradiation of estrone methane
sulfonate 4 did not provide the expected photo-Fries photoproducts while a noticeable distinct product
distribution (4a, 4b and 6) was obtained depending on the reaction solvent (see Table 3 and Scheme
5). This behavior was attributed to the intramolecular singlet-singlet energy transfer process followed
by the C(O)-C homolytic bond fragmentation that finally, the methyl group epimerizes via a Norrish
Type I reaction. Concurrently, irradiation of estrone aryl and methyl sulfonates in acetonitrile released
aryl and methane sulfonic acids behaving as efficient photoacid generators (PAGs) (Table 1 and
Figure 4). Indeed, the increase of the acidity in the reaction medium with irradiation time (see Figure
4) promotes a thermal hydrolysis of the estrone aryl and methyl sulfonates giving cleanly estrone (5)
that in turn, was converted into lumiestrone (6) (Scheme 8). Finally, the photochemistry of 17-
norestrone benzene sulfonate (8) and methane sulfonate (9) in methanol and cyclohexane gives
smoothly the expected ortho-regioisomers in good yields along with 17-norestrone (7) (see Scheme 6)
and no epimerization of the photoproducts was observed because there is no carbonyl group at the ring
D of the steroid. Therefore, the Norrish Type I reaction does not compete with the photo-Fries
rearrangement reaction. Therefore, we can suggest that this synthetic methodology would be useful in
the preparation of other kinds of aryl and alkyl sulfone steroid derivatives belonging to the family of
estrone through the photo-Fries rearrangement without interference of the Norrish Type I reaction.
Further studies on the preparation of fused 4-chromanone estrone derivatives applying the photo-Fries
rearrangement reaction of 3-(3-methylbutenyloxy) estrone derivatives are currently in progress in our
laboratory and will be reported in due course.
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ACKNOWLEDGEMENTS: Partial support for this work from the University of Buenos Aires,
Subsidio 20120160100124BA-Programa: 2017 – 2020. SMB and JAR are research members of
CONICET. MIQ thanks CONICET for doctoral scholarship (Doctorate Program).
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the
end of the article:
UV-visible spectral change vs time of compound 1 and relative absorbance at 330 nm (A/A∞) of
formation of ortho-rearranged photoproducts (1a, 1b and 1c) in cyclohexane, physical and
spectroscopical data of substrates and photoroducts and copies of 1D and 2D NMR spectra of
substrates and photoproducts.
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FIGURE CAPTIONS
Figure 1. Figure 1. (a) UV-visible spectral change vs time of 2 in methanol. Blue line: initial time;
red line: 14 min. (b) UV-visible spectral change vs time of 3 in cyclohexane. Blue line: initial time;
red line: 32 min. (c) Relative yield profile vs time of 2 in methanol: 2, 2a, 2b, 2c, 5, 6. (d) Relative
absorbance at 290 nm (A/A∞) of formation of ortho-rearranged photoproducts (2a, 2b and 2c) in:
cyclohexane (blue squares) and methanol (black circle).
Figure 2. Figure 2. Evolution of the consumption of estrone 5 into lumiestrone 6 during the
irradiation of estrone 2 in methanol followed by NMR spectroscopy.
Figure 3. Relative yield profile vs time of 4 in acetonitrile: 4, 4a and 6.
Figure 4. (a) Potentiometric titration curves of estrone benzene sulfonate (1) at different irradiation
time. (b) Sulfonic acid formed to estrone molar ratio as a function of irradiation time in different
solvents.
SCHEME CAPTIONS
Scheme 1. Photochemistry of some steroidal derivatives.
Chart I. Structures of the arylsulfonyl and alkylsulfonyl estrone derivatives.
Scheme 2. The photo-Fries rearrangement of estrone aryl sulfonate (1 – 3).
Scheme 3. The Norrish Type I photoreaction of compound (2a) and estrone (5) in organic solvents.
Scheme 4. Intramolecular proton transfer and radiationless processes of compounds 1b - 3b.
Scheme 5. (a) Product distribution obtained after irradiation of estrone methyl sulfonate (4) and (b)
Plausible reaction mechanism for the formation of photoproduct 4b.
Scheme 6. Preparation and irradiation of 17-norestrone 8 and 9.
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Scheme 7. Sulfonic acid release upon irradiation of estrone derivatives 1, 3 and 4.
Scheme 8. Proposed reaction mechanism of estrone aryl sulfonates 1, 2 and 3.
Scheme 9. Plausible mechanism for intramolecular energy transfer for aryl antenna to the C17-keto
group of estrone derivatives (5; 1a; 2b; 3a).
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Table 1. Irradiation of estrone arylsulfonates 1 – 3 in different solvents under N2 atmosphere.
Yield of photoproductsa and reaction quantum yield (R).b
Yields (%)
Estrone
Solvent
MeOH
R
arylsulfonates
1a 1b 1c
5
6
30
7
17 32
-
4
-
13
11
60
-
0.010
0.020
0.010
NMc
R
Cyclohexane 14 48
1
MeCN
THF
-
-
-
-
15
100
6
-
2ª
2b 2c
5
MeOH
16 40
1
5
-
24
10
22
5
10
4
0.011
0.006
0.003
Cyclohexane 15 39
2
3
MeCN
-
-
15
6
3ª
3b 3c
MeOH
15 35
-
18
22
8
0.002
0.004
0.003
Cyclohexane 11 47 11 14
MeCN 40
-
-
-
8
aYield of photoproducts determined by 1H-NMR spectroscopy in the reaction mixture.
Concentration of 3-acyl estrone: 5.0x10-3 M. bActinometer: KI (0.6 M), KIO3 (0.1 M) and
Na2B2O7.10H2O (0.01 M) in water; (I3 ) = 0.74; exc = 254 nm.(41) Error: ± 0.001. cNot
-
Measured.
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Table 2. Irradiation of estrone phenyl sulfonate in cyclohexane, acetone and the presence of
TMDO under N2 atmosphere.a
Additive
TMDOb
(mol.dm-3)
---
Yield (%)
1a 1b 1c
Estrone Solvent
5
6
Cyclohexane
Acetonec
14 48
4
-
11
7
---
-
-
41 15
Cyclohexane
5.0x10-4
1.0x10-3
1.5x10-3
23 43
26 51
28 56
7
5
-
5
1
-
2
-
1
-
1
aYield of photoproducts determined by H-NMR spectroscopy in the reaction mixture.
Concentration of estrone phenyl sulfonate: 1.0x10-3 M. Irradiation with exc = 254 nm.
bTetramethyl-1,2-diazetina dioxide (TMDO). cIrradiation with exc = 310 nm.
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